Study finds protein-protein interaction that contributes to Parkinson’s disease

In a study published in Nature Communication, a team led by Krembil Brain Institute Principal Scientists Drs. Lorraine Kalia and Suneil Kalia, and University of Toronto (U of T) professor Dr. Philip M. Kim have identified a protein-protein interaction that contributes to Parkinson’s disease.

In the disease, a protein called α-synuclein (a-syn) accumulates in the brain and leads to cell death. Much research is currently focused on eliminating a-syn with antibodies or using small molecules to prevent a-syn from aggregating. In this study, the researchers took an alternative approach by looking for protein-protein interactions that might promote a-syn accumulation in Parkinson’s disease.

Protein-protein interactions govern virtually all internal workings of the cell, including the breakdown of pathogenic proteins. Inhibiting certain interactions has emerged as a promising approach to treating diseases such as stroke and cancer.

“Identifying a particular interaction that contributes to a disease, and then finding ways to disrupt it, can be a laborious and incredibly slow process,” says Dr. Lorraine Kalia, who is also a neurologist at UHN and a scientist at the U of T’s Tanz. Center for Research on Neurodegenerative Diseases, at the Faculty of Medicine of Temerty.

“We all started out a little skeptical that we would have something useful in the end, and so the fact that we have something that warrants the extra work is way more than expected.”

According to Dr. Kim, the team took the opposite approach to accelerate the discovery of potential therapies. “We have developed a platform to screen molecules called peptide motifs; short chains of amino acids that can disrupt protein-protein interactions; for their ability to protect cells from a-syn. Once we identified the candidate peptides, we determined which protein-protein interactions they target.”

Using this approach, the team identified a peptide that reduced a-syn levels in cells by disrupting the interaction between a-syn and a protein subunit of the cellular machinery called the “sorting complex”. endosomal cell required for transport III” (ESCRT-III).

ESCRT-III is a component of a pathway that cells use to break down proteins, called the endolysosomal pathway. We found that a-syn interacts with a protein in ESCRT-III-;CHMP2B-;to inhibit this pathway, thereby preventing its own destruction.”

Dr. Lorraine Kalia, UHN Staff Neurologist

“We were impressed that the platform worked,” she adds. “But I think what was more interesting was that by doing this kind of screening, we were able to find an interaction that really wasn’t characterized before, and we also found a pathway that didn’t yet been targeted for therapeutics.”

According to Dr. Suneil Kalia, once the group identified this interaction, they confirmed that they could use their peptide to disrupt it, preventing a-syn from escaping the cell’s natural clearance pathways.

“We tested the peptide in several experimental models of Parkinson’s disease, and consistently found that it restored endolysosomal function, promoted a-syn clearance, and prevented cell death,” he said.

These results indicate that the a-syn-CHMP2B interaction is a potential therapeutic target for the disease, as well as other conditions that involve a-syn accumulation, such as dementia with Lewy bodies.

The next steps in this research are to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing studies are also determining the best approach for delivering potential therapies to the brain.

“This research is still in its infancy; more work is certainly needed to translate this peptide into a viable therapeutic,” warns Dr. Lorraine Kalia. “Nevertheless, our findings are very exciting as they suggest a new avenue for developing treatments for Parkinson’s disease and other neurodegenerative diseases.”

This study also highlights the value of multidisciplinary collaborations in health research.

“We simply could not have conducted this study in silos,” says Dr. Suneil Kalia. “The endolysosomal pathway is underexplored, so it was not an obvious place to look for possible disease-related protein-protein interactions. Dr. Kim’s screening platform was key in pointing us in the right direction. .”

“It’s amazing to see this platform – which we initially used to find potential cancer therapies – yield advances in brain research. The pathways cells use to stay healthy are fundamentally very similar from tissue to tissue. an organ system or disease could have important implications in other contexts,” says Dr. Kim.

“This is our first collaboration with Dr. Kim and it has been productive with a lot of synergy,” says Dr. Lorraine Kalia. “By researching technologies that are used in other fields and applying them to our own field, we hope this will accelerate research into Parkinson’s disease.”

She adds, “It really is brand new science and brand new targets that haven’t been central to drug development for Parkinson’s disease. We hope this will change the treatment landscape for this disease, which is so in need of new therapies.